The high-mobility group A1a/signal transducer and activator of transcription-3 axis: an achilles heel for hematopoietic malignancies?
The high-mobility group A1a/signal transducer and activator of transcription-3 axis: an achilles heel for hematopoietic malignancies?
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DOI：
10.1158/0008-5472.can-08-2121
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发表时间：
2008-12-15
期刊：
影响因子：
11.2
通讯作者：
Resar LM
中科院分区：
文献类型：
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作者：
Hillion J;Dhara S;Sumter TF;Mukherjee M;Di Cello F;Belton A;Turkson J;Jaganathan S;Cheng L;Ye Z;Jove R;Aplan P;Lin YW;Wertzler K;Reeves R;Elbahlouh O;Kowalski J;Bhattacharya R;Resar LM
虽然HMGA1（高迁移率组A1，原HMG-I/Y）是一种在侵袭性癌症中广泛过度表达的致癌基因，但HMGA1转化的分子机制才刚刚开始出现。HMGA1编码HMGA1a和HMGA1b蛋白亚型，具有调控基因表达的功能。为了确定HMGA1如何导致肿瘤转化，我们使用基因表达谱分析寻找受HMGA1调控的基因。在这里，我们发现编码信号分子信号换能器和转录激活因子3 （STAT3）的STAT3基因是HMGA1a的一个关键下游靶点。STAT3 mRNA和蛋白在过表达HMGA1a的成纤维细胞中上调，激活的STAT3再现了HMGA1a在成纤维细胞中的转化活性。在人白血病细胞中，HMGA1a也通过染色质免疫沉淀直接结合到STAT3启动子的保守区域，并在转染实验中激活STAT3启动子的转录。为了确定这一途径是否有助于hmga1介导的转化，我们在HMGA1a转基因小鼠中研究了STAT3的表达，所有小鼠都发展为侵袭性淋巴细胞恶性肿瘤。STAT3的表达在我们的转基因白血病细胞中增加，但在对照细胞中没有增加。阻断STAT3功能可诱导转基因白血病细胞凋亡，而在对照组中没有。在原发性人类白血病样本中，HMGA1a与stat3mrna呈正相关。此外，阻断STAT3在人类白血病或淋巴瘤细胞中的功能会导致细胞运动和病灶形成下降。我们的研究结果表明，HMGA1a - stat3轴是一个潜在的致命弱点，可以用于治疗过表达HMGA1a的造血和其他恶性肿瘤。
Although HMGA1 (high-mobility group A1; formerly HMG-I/Y) is an oncogene that is widely overexpressed in aggressive cancers, the molecular mechanisms underlying transformation by HMGA1 are only beginning to emerge. HMGA1 encodes the HMGA1a and HMGA1b protein isoforms, which function in regulating gene expression. To determine how HMGA1 leads to neoplastic transformation, we looked for genes regulated by HMGA1 using gene expression profile analysis. Here, we show that the STAT3 gene, which encodes the signaling molecule signal transducer and activator of transcription 3 (STAT3), is a critical downstream target of HMGA1a. STAT3 mRNA and protein are up-regulated in fibroblasts overexpressing HMGA1a and activated STAT3 recapitulates the transforming activity of HMGA1a in fibroblasts. HMGA1a also binds directly to a conserved region of the STAT3 promoter in vivo in human leukemia cells by chromatin immunoprecipitation and activates transcription of the STAT3 promoter in transfection experiments. To determine if this pathway contributes to HMGA1-mediated transformation, we investigated STAT3 expression in our HMGA1a transgenic mice, all of which developed aggressive lymphoid malignancy. STAT3 expression was increased in the leukemia cells from our transgenics but not in control cells. Blocking STAT3 function induced apoptosis in the transgenic leukemia cells but not in controls. In primary human leukemia samples, there was a positive correlation between HMGA1a and STAT3 mRNA. Moreover, blocking STAT3 function in human leukemia or lymphoma cells led to decreased cellular motility and foci formation. Our results show that the HMGA1a–STAT3 axis is a potential Achilles heel that could be exploited therapeutically in hematopoietic and other malignancies overexpressing HMGA1a.